Abstract
The Neuregulin-1 (Nrg1) signaling pathway has been widely implicated in many aspects of heart development including cardiac trabeculation. Cardiac trabeculation is an important morphogenetic process where clusters of ventricular cardiomyocytes extrude and expand into the lumen of the ventricular chambers. In mouse, Nrg1 isoforms containing an immunoglobulin-like (IgG) domain are essential for cardiac trabeculation through interaction with heterodimers of the epidermal growth factor-like (EGF-like) receptors ErbB2/ErbB4. Recent reports have underscored the importance of Nrg1 signaling in cardiac homeostasis and disease, however, placental development has precluded refined evaluation of the role of this pathway in mammals. ErbB2 has been shown to have a developmentally conserved role in cardiac trabeculation in zebrafish, a vertebrate model organism with completely external development, but the requirement for Nrg1 has not been examined. We found that among the multiple Nrg1 isoforms, the IgG domain-containing, type I Nrg1 (nrg1-I) is the only isoform detectable in the heart. Then, using CRISPR/Cas9 gene editing, we targeted the IgG domain of Nrg1 to produce novel alleles, nrg1nc28 and nrg1nc29, encoding nrg1-I and nrg1-II truncations. Our results indicated that zebrafish deficient for nrg1-I developed trabeculae in an ErbB2-dependent manner. Further, these mutants survive to reproductive adulthood with no overt cardiovascular defects. We also found that additional EGF-like ligands were expressed in the zebrafish heart during development of trabeculae. Together, these results suggest that Nrg1 is not the primary effector of trabeculation and/or that other EGF-like ligand(s) activates the ErbB2/ErbB4 pathway, either through functioning as the primary ligand or acting in a redundant manner. Overall, our work provides an example of cross-species differences in EGF family member requirements for an evolutionary conserved process.
Highlights
Congenital heart diseases (CHD) are highly prevalent birth defects [1] and often feature perturbations in cardiac morphogenesis that arise during development [2,3,4]
All isoforms share an epidermal growth factor-like domain (EGF), a transmembrane domain (TM), and a C-terminal neuregulin domain (Fig 1B and 1C)
This study highlights an example of cross-species differences in EGF family member requirements for the process of cardiac trabeculation
Summary
Congenital heart diseases (CHD) are highly prevalent birth defects [1] and often feature perturbations in cardiac morphogenesis that arise during development [2,3,4]. The Nrg1-ErbB2/4 signaling pathway has been implicated in many aspects of vertebrate cardiac biology ranging from heart development to homeostasis and disease [5]. Nrg binds to cardiomyocyte-expressed ErbB4 via its epidermal growth factor (EGF) domain. This ligand and receptor interaction subsequently stimulates hetero-dimerization of ErbB4 with its essential co-receptor ErbB2, leading to activation of ErbB2 tyrosine kinase activity and downstream signaling [10,11,12]. Recent reports have underscored the importance of the Nrg1-ErbB2/4 signaling pathway in cardiac repair processes, and recombinant Nrg is currently in clinical trials as a heart failure therapeutic, but the role of Nrg in development is largely unknown [5,13,14,15,16,17,18,19]. A refined understanding of this role could provide insight into CHDs or inform the development of improved therapeutics
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